DESCRIPTION(From applicant's abstract): The proposed studies are designed to examine if the transcription factor CREB (cAMP response element binding protein) in the nucleus accumbens shell (NASh) plays a role in depression. Although the NASh is involved in the hedonic (pleasurable) effects of food, sex, and addictive drugs, little is known about its involvement in mood disorders. We found previously that blockade of CREB function in the NASh increases cocaine reward in rats, whereas elevated CREB function in this region eliminates cocaine reward. Because anhedonia (a diminished ability to experience pleasure) is a hallmark symptom of depression, these data suggest that CREB (and genes regulated by CREB) in the NASh may be involved in depressive syndromes. To address this question, we have examined relationships between CREB function in the NASh and behavior in the Porsolt forced swim test (FST), a model of depression. In preliminary studies, we find that exposure to the FST causes immediate increases in phospho-CREB (P-CREB, an activated form of CREB) in the NASh. To examine the significance of this effect, we elevated CREB expression in the NASh by viral-mediated gene transfer. This treatment increases immobility in the FST (suggesting increased depression), whereas blockade of CREB function in the NASh (by overexpression of a dominant negative CREB) decreases immobility (suggesting an antidepressant effect). Together, our work suggests that CREB in the NASh is a molecular regulator of at least some symptoms of depression (anhedonia, despair). We propose to further examine the interaction of CREB (and CREB-regulated genes) in the NASh with two antidepressants (desipramine, fluoxetine) in the FST. First, we will determine if antidepressants block CREB-induced increases in immobility. Second, we will examine the time course of FST-induced P-CREB elevations in the NASh, and determine if they are blocked by antidepressants. Third, we will determine if the FST increases expression of dynorphin, a target gene of CREB. Fourth, we will determine if blockade of the brain receptors for dynorphin (k opioid receptors) has antidepressant actions. Finally, we will use intracranial self-stimulation (ICSS) to examine if elevated CREB expression in the NASh produces symptoms of depression in a second behavioral assay. These studies may establish that elevated CREB expression in the NASh is a "molecular trigger" for depression, and identify novel targets for pharmacotherapies.